Erectile dysfunction (ED) is a frequent complication of type 2 diabetes that impairs quality of life for up to 75% of men with diabetes. ED strongly correlates with insulin resistance, obesity, and the metabolic syndrome. The long-term goal of this research is to elucidate the poorly understood pathogenesis of ED in diabetic and pre- diabetic states. The brain serves a key role in healthy erectile function by initiating sexual desie and by controlling autonomic erectile responses. Melanocortin pathways, consisting of POMC neurons that produce a- MSH and downstream MC3 and 4 receptor (MC4R)-containing neurons, are critical for these processes. However, therapeutics targeting MC receptors have the disadvantage of altering blood pressure and heart rate. The objective of this proposal is to determine if reduced endogenous a-MSH production can lead to ED and to identify the neuronal circuitry to which POMC neurons project to uniquely control erectile function. MC4Rs are found on oxytocin neurons to which POMC neurons project, and administration of a-MSH, MC4R agonists, or oxytocin increases sexual motivation, elicits sexual behaviors, and causes penile erection in mice and humans. The central hypothesis is that insulin and leptin resistance in POMC neurons promotes ED by reducing aMSH production and oxytocin signaling. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants' laboratories and will be tested with three specific aims: 1) Determine whether impaired insulin and leptin signaling in POMC neurons alters erectile function, 2) Determine whether restoring neuronal insulin and leptin sensitivity and a-MSH production improves sexual performance, and 3) Determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function. Under the first aim, novel cell type-specific tools will be used to allow acute neuronal manipulation to examine the role of POMC-specific insulin and leptin resistance in ED in a unique mouse model of prediabetes. In the second aim, the applicants will then determine whether reactivating hypothalamic leptin and insulin pathways restores normal sexual function and offers a potential treatment strategy in cases of central insulin and leptin resistance caused by diet-induced obesity. Under the third aim, the applicants will determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function using pharmacogenetics to examine whether this pathway is necessary and sufficient. A well-established cre-dependent viral tracer will then be employed to map downstream circuitry. The rationale for these studies is that they will be the first to address whether diabetes is accompanied by defective melanocortin signaling that may cause or exacerbate ED. The rising number of men with obesity and type 2 diabetes makes this research highly significant. Given the involvement of melanocortin pathways in regulating blood pressure, obesity, and glycemic control, the proposed research has the potential to guide the development of novel and effective therapies devoid of side effects that improve both the quality of life and overall health of these patients.